Bilateral Tonic Pupils Due to Antidisialoganglioside Antibody Immunotherapy for Neuroblastoma

Atonic pupil results from postganglionic parasympathetic pupillomotor denervation, leading classically to mydriasis, poor reaction to light with or without preservation of constriction to accommodation (light-near dissociation), and cholinergic hypersensitivity.

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Bilateral Tonic Pupils Due to Antidisialoganglioside Antibody Immunotherapy for Neuroblastoma Cole Swiston, MD, Abigail Jebaraj, MD, Sravanthi Vegunta, MD, Judith Warner, MD A tonic pupil results from postganglionic parasympathetic pupillomotor denervation, leading classically to mydriasis, poor reaction to light with or without preservation of constriction to accommodation (light-near dissociation), and cholinergic hypersensitivity. Although many cases are idiopathic (Adie tonic pupil), any process which disrupts the postganglionic pupillary fibers can lead to a tonic pupil (1). We present a unique case of bilateral tonic pupils due to the antidisialoganglioside (GD2) chimeric monoclonal antibody, dinutuximab. Our patient is an 8-year-old boy who presented to the emergency room for evaluation of abnormal pupils, who had been diagnosed with Stage 4 neuroblastoma 4 years prior, now in remission. He was initially diagnosed in February 2017 after presenting with bilateral leg pain and refusal to ambulate. Imaging revealed a right suprarenal mass and extensive skeletal metastatic involvement, confirmed as poorly differentiated neuroblastoma with bilateral bone marrow biopsy. Starting from February 2017, he was treated with 6 cycles of cyclophosphamide and topotecan which ended in July 2017. His primary adrenal tumor was resected in June 2017. Of note, before dinutuximab immunotherapy, he underwent tandem autologous bone marrow transplants which were completed in October 2017 and radiation to the adrenal region (21.6 cGy to the primary tumor site) was completed in January 2018. The patient began dinutuximab immunotherapy in January 2018, which was dosed at 14 mg per day for 4 days (17.5 mg/m2/day), repeated every 28 days for 5 months, ending in June 2018. He had neuropathic pain at the onset of infusion which resolved between doses. After the second of 5 infusions of dinutuximab, the patient developed photophobia and dilated pupils. The dinutuximab dose was then reduced by 50% for his fourth and fifth cycles, and he was referred to pediatric ophthalmology at that time. Examination revealed bilateral mydriatic pupils (9 mm) with no reaction to light. These findings were attributed to the immunotherapy. He was evaluated with repeat imaging in John A. Moran Eye Center, Salt Lake City, Utah. Supported in part by an Unrestricted Grant from Research to Prevent Blindness, New York, NY, to the Department of Ophthalmology and Visual Sciences, University of Utah. The authors report no conflicts of interest. Address correspondence to Cole Swiston, MD, Moran Eye Center, 65 South Mario Capecchi Dr., Salt Lake City, UT 84132; E-mail: Cole. [e-mail] Swiston et al: J Neuro-Ophthalmol 2023; 43: e53-e54 July 2018 after completing his treatment, was found to be tumor free, and has been in remission since that time. At the age of 8, he presented to the emergency room after developing a migraine-type headache with unequal large pupils noted by his school nurse. Bedside ophthalmologic evaluation was notable for bilateral mydriatic pupils and anisocoria. The right pupil slowly constricted from 7 mm to 5 mm to light. The left pupil was 5 mm with minimal reaction to light. The remainder of his ophthalmologic examination and dilated fundus examination was normal. An MRI of the brain was ordered as well as serum laboratories to rule out recurrent neuroblastoma, all of which were unremarkable. The patient was then referred to the neuro-ophthalmology clinic. Two weeks later in the neuro-ophthalmology clinic, the patient’s acuity was 20/20 in each eye. Both pupils were dilated and minimally reactive to light, with the right pupil at 6 mm and the left pupil at 5 mm in room light (Fig. 1A). Light-near dissociation was present. Visual fields were full to confrontation, and his sensorimotor examination was normal. Color vision and stereopsis were full. Slit-lamp examination revealed irregular pupillary margins, with vermiform movements. After instillation of 0.125% pilocarpine bilaterally, both pupils constricted. After 30 minutes, the right pupil was 3 mm and the left pupil was 2.5 mm, indicating cholinergic hypersensitivity (Fig. 1B). Ocular coherence tomography of his retinal nerve fiber layer was normal. Deep tendon reflexes were absent in the upper and lower extremities. Because the patient’s mydriasis had been present for 4 years after treatment, we counseled his parents that his pupillary function would likely not recover. Were he to develop photophobia in the future, he could use dilute pilocarpine drops to constrict his pupils. The patient did not have photophobia. Our patient’s pupillary findings were consistent with bilateral tonic pupils due to dinutuximab. This novel immunotherapy is a chimeric monoclonal antibody that targets tumor-associated GD2, which is found in abundance on the tumor cell surface in contrast to limited systemic cellular concentrations. The drug is used in combination with isotretinoin, interleukin-2, and colonystimulating factors during the maintenance phase of multimodal oncologic therapy for high-risk neuroblastoma. GD2 is also found in the paranodal myelin of the central nervous system, on peripheral sensory nerves, and has been isolated from the ciliary muscle and iris tissue. The major adverse effect of dinutuximab is severe neuropathic pain with onset during infusions, subsiding within hours of completion. e53 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. External photographs. A. In room light, the right pupil is 6 mm and the left pupil is 5 mm. B. Thirty minutes after instillation of one drop of 0.125% topical pilocarpine to each eye, the right pupil is 3 mm and the left pupil is 2.5 mm. Fever, hypersensitivity, hypotension, and capillary leak syndrome have also been reported (2). In addition to systemic neurotoxicity, ocular side effects have also been reported, generally involving pupillary changes. Tse et al performed a retrospective review of 38 patients treated with dinutuximab who had ophthalmologic evaluations. Thirty-four percent of study patients demonstrated pupillary mydriasis in a dosedependent manner (3). Kremens et al similarly found 10 of 106 patients treated with anti-GD2 antibodies developed mydriasis, one of which was found to have hypersensitivity and constriction to pilocarpine 0.1%. All of these patients had at least partial improvement in pupillary constriction within a few months to approximately 1 year, regardless of cessation of the drug (4). Tse et al reported a median time to the onset of mydriasis of 5.5 days (mean 19.2 days; range 5–75 days), and median time to the onset of impaired accommodation was 12.5 days (mean 18 days; range 3–63 days). Of the 5 patients who developed mydriasis only, 2 had resolution at a median of 95 days after discontinuation of treatment. The common practice in the oncologic literature is to reduce the dinutuximab dose by 50% at the first sign of persistent pupillary mydriasis. The hypothesized mechanism of mydriasis in these patients is ocular parasympathetic disruption because e54 GD2 has been isolated in the ciliary muscle and iris (5). Interestingly, there have been no other reports of adverse effects hypothesized to relate to parasympathetic nerve disruption, and the true mechanism is still unknown. In summary, our patient presented with bilateral mydriatic pupils, light-near dissociation, vermiform iris movements, and cholinergic hypersensitivity, which further supports the theory that dinutuximab disrupts postganglionic parasympathetic pupillomotor fibers resulting in tonic pupils. Although previous reports have suggested this, none have reported the classic findings of tonic pupils. This case not only represents a unique cause of tonic pupils but also may benefit future clinicians to safely dose dinutuximab and prevent unnecessary imaging studies prompted by pupillary changes. STATEMENT OF AUTHORSHIP Conception and design: A. Jebaraj, S. Vegunta, J. Warner; Acquisition of data: A. Jebaraj, S. Vegunta, J. Warner; Analysis and interpretation of data: A. Jebaraj, S. Vegunta, J. Warner. Drafting the manuscript: A. Jebaraj, S. Vegunta, J. Warner; Revising it for intellectual content: A. Jebaraj, S. Vegunta, J. Warner. Final approval of the completed manuscript: A. Jebaraj, S. 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Biochim Biophys Acta. 1994;1214:115–123. Swiston et al: J Neuro-Ophthalmol 2023; 43: e53-e54 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.